利妥昔单抗在淋巴瘤维持治疗中的新进展

利妥昔单抗是第一个被批准用于淋巴瘤治疗的单克隆抗体。在弥漫大B细胞性淋巴瘤、滤泡淋巴瘤等B细胞非霍奇金淋巴瘤中取得了显著疗效。对于诱导治疗获得缓解后的滤泡淋巴瘤,利妥昔单抗维持治疗可进一步改善患者预后,为治疗指南所推荐。随着淋巴瘤治疗方案的不断改进,如何更好地把握维持治疗的适应症并进一步优化现有的治疗策略,成为研究的热点。本文通过总结分析近年来的相关文献,对利妥昔单抗用于淋巴瘤维持治疗的最新进展进行综述。      

曲妥珠单抗用于乳腺癌辅助治疗的基本原则与策略

曲妥珠单抗 (赫赛汀) 的问世开辟了乳腺癌靶向治疗的先河,目前全球至少有6项前瞻性随机对照临床试验证实了曲妥珠单抗可以显著提高Her-2阳性乳腺癌患者的无病生存率和总生存率.本文对上述临床试验的数据进行了详细的解读,并结合目前我国临床实际情况提出了曲妥珠单抗用于辅助治疗的基本原则以及个体化的治疗策略,为广大乳腺癌临床工作者提供参考.     

靶向HER-2受体二聚化的新药——帕妥珠单抗研究进展

帕妥珠单抗（pertuzumab）系新一代人源化单克隆抗体类药物,通过与HER-2胞外受体结构域Ⅱ区的结合,特异性地抑制HER-2受体二聚化。实验研究表明,帕妥珠单抗联合曲妥珠单抗能够更全面地阻断HER-2的信号转导。2012年6月FDA批准帕妥珠单抗用于联合曲妥珠单抗和多西他赛治疗HER-2阳性的转移性乳腺癌,2013年9月30日FDA进一步加速批准该方案作为新辅助治疗用于高风险HER-2阳性的早期乳腺癌。本文全面回顾了帕妥珠单抗的研究进展,并重点介绍该药的临床试验情况,以期为帕妥珠单抗的临床实践应用提供相关的参考依据。     

拉帕替尼在乳腺癌中的应用及其耐药机制研究现状

随着分子肿瘤学的发展,乳腺癌进入了分子分型时代。基于患者不同生物标志物表达的个体化医疗已经成为目前乳腺癌治疗的模式。HER2阳性乳腺癌侵袭性高、预后差,占所有乳腺癌患者的20%~30%。曲妥珠单抗作为第一个人源化单克隆抗体,以HER2为靶点,改善了这部分患者的预后,因此乳腺癌相关各大临床实践指南和专家共识明确推荐HER2阳性乳腺癌患者不同阶段均可以使用曲妥珠单抗进行抗HER2治疗。但是曲妥珠单抗的心脏毒性及原发、继发耐药等问题迫使临床医生对二线抗HER2治疗进行探索。拉帕替尼作为第一个被批准用于临床作用于HER1和HER2双靶点的酪氨酸激酶抑制剂,是曲妥珠单抗失败后的不错选择。本文对拉帕替尼在乳腺癌中的应用、相关临床研究及其耐药机制研究进行简要综述。     

卡瑞利珠单抗在消化系统肿瘤中的应用研究进展

随着免疫检查点抑制剂（ICI）的广泛应用,许多晚期消化系统恶性肿瘤患者迎来了新的希望。起初,ICI的使用依赖于进口,随着中国制药业不断发展,越来越多的国产ICI获批应用于临床。卡瑞利珠单抗作为国产的程序性死亡受体1(PD-1)抑制剂之一,自2019年在中国获批上市后,适应证从霍奇金淋巴瘤、肺癌不断扩展到食管癌、肝癌等消化系统恶性肿瘤。本文综述了卡瑞利珠单抗在消化系统肿瘤中的应用研究进展。     

曲妥珠单抗原发耐药与继发耐药的研究进展

“曲妥珠单抗耐药”概念于2001年基于细胞系和动物模型的实验研究被首次提出,此后众多研究从不同的角度探索曲妥珠单抗耐药的分子机制。目前若干曲妥珠单抗耐药机制的研究已经单独针对原发耐药或继发耐药机制进行,本文对其研究结果进行综述。原发耐药与继发耐药机制的差异提示我们,在曲妥珠单抗治疗中应该根据不同的临床耐药患者亚群给予相应的临床治疗策略。     

奥滨尤妥珠单抗治疗CD20阳性复发/难治非霍奇金淋巴瘤的研究进展

由于利妥昔单抗的应用,大部分CD20（+）的非霍奇金淋巴瘤的疗效得到了提高,但部分患者对利妥昔单抗不敏感,也有部分患者出现耐药而导致复发。奥滨尤妥珠单抗为新一代抗CD20单抗,与利妥昔单抗相比具有高效性、耐受性好、毒副作用小的特征。本文阐述了奥滨尤妥珠单抗的药物作用机制,在治疗CD20阳性的非霍奇金淋巴瘤临床试验中的疗效及不良反应。     

曲妥珠单抗在HER-2阳性乳腺癌患者新辅助治疗中的应用研究进展

曲妥珠单抗是人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）的特异性抑制剂,在HER-2阳性乳腺癌患者新辅助治疗中的应用日益广泛。大规模的随机、对照临床试验证实,新辅助化疗联合曲妥珠单抗与单纯化疗比较能显著提高病理完全缓解（pathologic complete response,pCR）率。在曲妥珠单抗联合化疗的基础上加用拉帕替尼较单用曲妥珠单抗可大大提高pCR率。蒽环与非蒽环类化疗药物均可作为曲妥珠单抗的联合用药,内分泌治疗也可作为雌激素受体阳性患者的联合用药。pCR是曲妥珠单抗新辅助治疗后生存获益的独立预后因素,HER-2转阴而未达到pCR的患者为不良预后因素。本文将对曲妥珠单抗在HER-2阳性乳腺癌患者新辅助治疗中的研究进展进行综述。      

乳腺癌患者曲妥珠单抗治疗失败后Margetuximab的应用研究进展

人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阳性乳腺癌是乳腺癌中最具侵袭性的亚型,恶性程度高且易发生转移。尽管曲妥珠单抗作为HER2阳性晚期乳腺癌一线靶向药物取得了巨大成功,但仍有部分患者存在心脏毒性及耐药性问题。相比曲妥珠单抗,Margetuximab的Fc段得到优化,其对曲妥珠单抗治疗后进展的HER2阳性乳腺癌也有一定作用,在后曲妥珠时代仍有一席之地。全文对Margetuximab的结构特点、作用机制、药效学、药物代谢动力学及临床研究作一综述,为其临床用药提供参考。     

滤泡性淋巴瘤治疗中的疑惑和应对策略

 【摘要】 在过去的5年中,滤泡性淋巴瘤的治疗发生了很大的变化。很多抗肿瘤新药应用到一线治疗和维持治疗中,对于复发难治的滤泡性淋巴瘤的治疗策略也有了新的改变。尽管在国际上能够看到这些新的进展,但临床上仍有很多问题有待解决。本文对利妥昔单抗应用的有效性和安全性进行了讨论,对复发难治的滤泡性淋巴瘤的治疗策略进行了整理和展望,并对近年来开展的新药临床试验进行了介绍。     

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma

Obinutuzumab (Gazyva^®, Gazyvaro^®) is a recombinant, monoclonal, humanized and glycoengineered, type II, anti-CD20, IgG1 antibody. It has recently been granted an additional indication for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen. In the primary analysis of the large, phase III GADOLIN study, induction therapy with obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolonged progression-free survival (PFS) to a statistically significant extent relative to induction with bendamustine monotherapy in patients with indolent non-Hodgkin’s lymphoma (iNHL). The improvement in PFS was largely driven by the subgroup of patients with follicular lymphoma, who also had prolonged overall survival (OS) in a planned updated analysis. Obinutuzumab had a generally manageable tolerability profile in these patients; mild to moderate infusion-related reactions (IRRs) were the most common treatment-emergent adverse events (AEs) and neutropenia the most common grade 3 or 4 treatment-related AEs. Although additional studies and longer-term data are needed to further assess treatment benefits with obinutuzumab, current evidence indicates that obinutuzumab is a useful treatment option for patients with rituximab-refractory or -relapsed follicular lymphoma.     

Management of patients with follicular lymphoma treated first line with obinutuzumab

Recently, obinutuzumab was included in the Australian Pharmaceutical Benefits Scheme for use in first line, advanced or bulky stage 2, follicular lymphoma, providing more immunochemotherapy treatment options available than ever before. Rituximab with chemotherapy has been the standard of care since reimbursement in the late 1990s; however, obinutuzumab‐based regimens have shown superior progression‐free survival in comparison to rituximab‐based options, albeit at an increased risk of grade ≥3 adverse events. As median overall survival approaches 20 years or more, the long‐term effects and sequencing of any strategy should be considered. Here we discuss the considerations for selection of front‐line therapy, based on evidence and local Australian clinician experience, in the management of first line follicular lymphoma.     

Rituximab maintenance therapy in indolent NHL: a clinical review

Rituximab maintenance therapy following successful induction has emerged as a highly effective treatment for follicular lymphoma. Several randomized trials have been conducted analyzing the impact of rituximab maintenance compared to observation alone on treatment outcome. These studies have been conducted in patients receiving single-agent rituximab, standard chemotherapy or rituximab plus chemotherapy as initial cytoreduction, in both previously treated and untreated patients. In all the trials, rituximab maintenance resulted in a clinically and statistically significant benefit in clinical endpoints such as progression-free survival. Moreover, first data indicate that rituximab maintenance can prolong overall survival in patients with follicular lymphoma. These data have established rituximab maintanance as an important part of multimodal therapeutic strategies. Ongoing studies will help to determine the best schedule for the maintenance therapy in the treatment of follicular lymphoma.     

Rituximab and its role as maintenance therapy in non-Hodgkin lymphoma

Since rituximab, a chimeric monoclonal anti-CD20 antibody, was introduced into clinical practice in 1997, data regarding its benefit in terms of response rate, quality of response, progression-free survival and overall survival in B-cell lymphoid malignancies continues to expand. Rituximab has proven to be a relatively well-tolerated drug, with its major side effects being infusion related. Rituximab was approved initially by the US FDA and the European Medicines Agency for relapsed or refractory low-grade or follicular CD20+ B-cell non-Hodgkin lymphomas. Subsequently, its use has been extended to include first-line therapy in low-grade lymphoma as well as the treatment of more aggressive histological subtypes such as diffuse large B-cell lymphoma. In this article, we review the landmark trials that have impacted clinical practice in follicular and diffuse large B-cell lymphomas and the emerging data for use of rituximab as maintenance therapy in non-Hodgkin lymphoma.     

Update on front-line therapy for follicular lymphoma: chemo-immunotherapy with rituximab and survival

Over the last three decades, there has been a wide range of options in the management of follicular lymphoma, including observation (watching and waiting), single-agent or combination (e.g., alkylating agents, anthracyclines or purine nucleoside analogs) radiation therapy, immunotherapy alone or in combination with chemotherapy, and interferon. A number of trials studying the treatment of follicular lymphoma patients have investigated the benefit of adding rituximab either concurrently or sequentially to chemotherapy. In the current review, these studies were selected based on the fact that they were randomized Phase III studies with two arms comparing chemotherapy alone with rituximab-based chemo-immunotherapy regimens. In September 2006, the US FDA approved the use of rituximab (Rituxan) as front-line treatment of patients with follicular lymphoma in combination with cyclophosphamide, vincristine and prednisone (R-CVP) as well as for the treatment of patients with low-grade non-Hodgkin's Lymphoma who achieve stable disease or better following first-line treatment with the same chemotherapy regimen (CVP --> R). The European Medicines Agency also approved the use of rituximab (MabThera) as front-line treatment of patients with stage III-IV disease in combination with CVP chemotherapy. In conclusion, although the clinical studies discussed in this article provide evidence for a progression-free survival benefit, overall survival advantage was clearly shown for the first time in a recent update of the initial study in patients with follicular lymphoma.     

Antilymphoma treatments given subsequent to Yttrium 90 ibritumomab tiuxetan are feasible in patients with progressive non-Hodgkin's lymphoma: a review of the literature

Yttrium 90-labeled ibritumomab tiuxetan is approved for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). To date, the efficacy of repeated courses of radioimmunoconjugate treatment in patients whose disease has progressed has not been studied as a formal endpoint in a clinical trial setting. However, several clinical studies have been conducted in patients with progressive NHL who had previously received 90Y ibritumomab tiuxetan. A retrospective review of these studies has shown that clinical responses have been achieved with all types of subsequent treatment with no apparent impact on their efficacy. In addition, no significant differences in toxicities with subsequent therapies have been observed between patients who had previously received 90Y ibritumomab tiuxetan therapy and those who had not. These findings suggest that patients previously treated with 90Y ibritumomab tiuxetan can feasibly undergo other forms of treatment for progressive NHL, and that a clinical response to further treatment options is not precluded by administration of 90Y ibritumomab tiuxetan.     

Update on front-line therapy for follicular lymphoma: chemo-immunotherapy with rituximab and survival

Over the last three decades, there has been a wide range of options in the management of follicular lymphoma, including observation (watching and waiting), single-agent or combination (e.g., alkylating agents, anthracyclines or purine nucleoside analogs) radiation therapy, immunotherapy alone or in combination with chemotherapy, and interferon. A number of trials studying the treatment of follicular lymphoma patients have investigated the benefit of adding rituximab either concurrently or sequentially to chemotherapy. In the current review, these studies were selected based on the fact that they were randomized Phase III studies with two arms comparing chemotherapy alone with rituximab-based chemo-immunotherapy regimens. In September 2006, the US FDA approved the use of rituximab (Rituxan^®) as front-line treatment of patients with follicular lymphoma in combination with cyclophosphamide, vincristine and prednisone (R-CVP) as well as for the treatment of patients with low-grade non-Hodgkin’s Lymphoma who achieve stable disease or better following first-line treatment with the same chemotherapy regimen (CVP → R). The European Medicines Agency also approved the use of rituximab (MabThera^®) as front-line treatment of patients with stage III–IV disease in combination with CVP chemotherapy. In conclusion, although the clinical studies discussed in this article provide evidence for a progression-free survival benefit, overall survival advantage was clearly shown for the first time in a recent update of the initial study in patients with follicular lymphoma.     

Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma

Conjugated antibodies have been in clinical trials for over 30 years. Immunotoxins, chemotherapy conjugates and radioimmunotherapies have been evaluated. Zevalin, the first conjugated antibody for the treatment of non-hodgkin's lymphoma (NHL) (and the first radioimmunotherapeutic for cancer) was approved by the US FDA on 19 February 2002 (approval is pending in the EEC). Zevalin (90Yttrium ibritumomab tiuxetan) has been in clinical trials since 1992. Several studies have been conducted including a randomized Phase III trial where it showed superiority to rituximab in overall response rate and in complete response rate. The current indications are: low-grade or follicular lymphoma refractory to rituximab, and relapsed or refractory, low-grade, follicular or transformed lymphoma. Additional studies have been initiated to further define the role of this new therapy in the treatment of patients with B-cell non-hodgkin's lymphoma.     

Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma

Conjugated antibodies have been in clinical trials for over 30 years. Immunotoxins, chemotherapy conjugates and radioimmunotherapies have been evaluated. Zevalin?, the first conjugated antibody for the treatment of non-hodgkin's lymphoma (NHL) (and the first radioimmunotherapeutic for cancer) was approved by the US FDA on 19 February 2002 (approval is pending in the EEC). Zevalin (⁹⁰Yttrium ibritumomab tiuxetan) has been in clinical trials since 1992. Several studies have been conducted including a randomized Phase III trial where it showed superiority to rituximab in overall response rate and in complete response rate. The current indications are: low-grade or follicular lymphoma refractory to rituximab, and relapsed or refractory, low-grade, follicular or transformed lymphoma. Additional studies have been initiated to further define the role of this new therapy in the treatment of patients with B-cell non-hodgkin's lymphoma.     

Increased vascularization predicts favorable outcome in follicular lymphoma.

PURPOSE: In malignant lymphoma, angiogenesis has been associated with adverse outcome or more aggressive clinical behavior. This correlation has been established in groups of patients with a large heterogeneity regarding lymphoma subtypes and treatment regimens. The aim of this study is to investigate the significance of vascularization in patients with follicular lymphoma receiving uniform first-line treatment. EXPERIMENTAL DESIGN: We assessed microvessel density (MVD) in pretreatment lymph node biopsies of 46 previously untreated patients with follicular lymphoma using anti-CD34 immunohistochemical staining and interactive quantification. In a selection of cases, vascular endothelial growth factor (VEGF)-RNA in situ hybridization was done. Patients were treated with cyclophosphamide-vincristine-prednisone induction chemotherapy combined with IFN-alpha2b. Thirty-six patients responded and received IFN-alpha as maintenance therapy. RESULTS: MVD ranged from 10 to 70 per measurement field of 0.19 mm2 (median, 38). Median progression-free survival was 47 months in patients with MVD in the highest tertile and only 13 months in patients with lower MVD. Overall survival in patients with low vessel density was 59 months. In patients with high vessel density, median overall survival was not reached. Multivariate analysis indicated that MVD was independently associated with overall survival. There was a lack of correlation between VEGF-RNA expression and vessel density. CONCLUSION: This study shows that in follicular lymphoma increased vascularization is associated with improved clinical outcome. Furthermore, VEGF-A expression seems not to be involved in follicular lymphoma angiogenesis.